Synapses are highly dynamic structures that are capable of enhancing or depressing their efficiency based on the pattern and intensity of their stimuli. This process is termed synaptic plasticity. The most frequently studied form of synaptic plasticity is long-term potentiation (LTP) in the CA 1 region of the hippocampus. The main goal of this project is to further understand the molecular mechanisms of LTP. The induction of LTP is critically dependent on the activation of N-methyl-D-aspartate-type glutamate receptors (NMDA-R) and Ca2+/Calmodulin-Dependent Kinase II (CaMKII). These two signaling molecules interact in an activity- dependent fashion through the cytosolic tails of two NMDA-R subunits NR1 and NR2B. These interactions are believed to recruit CaMKII to active postsynaptic signaling sites where it is thought to play a crucial role in orchestrating the molecular changes that accompany synaptic plasticity. Our laboratory has developed two strains of mice with targeted mutations to NR1 and NR2B that are deficient in their ability to bind to CaMKII. These strains of mice will be used to test the significance of CaMKII recruitment to these binding sites during LTP. I will use electrophyiological and Ca2+ imagining studies to characterize the effects of the targeted NR1 and NR2B point mutations on basal synaptic transmission and synaptic plasticity. The results of these studies will provide clear evidence to the importance of NMDA-R mediated CaMKII recruitment to the postsynaptic density during the induction of synaptic plasticity. These studies crucial for understanding physiologic changes in synaptic function, as in associative learning, and in pathological states involving synaptic changes including neurodegenerative diseases, psychiatric diseases, and cerebral ischemia. Mental wellbeing is emerging as one of the most important areas in public health. The results from our study will significantly contribute to our knowledge of synaptic transmission, which has been implicated in a wide range of mental health diseases including depression, substance abuse, and schizophrenia. [unreadable] [unreadable] [unreadable]